Divergent prion strain evolution driven by PrP^C expression level in transgenic mice.

Abstract

Prions induce a fatal neurodegenerative disease in infected host brain based on the refolding and aggregation of the host-encoded prion protein PrP^C into PrP^Sc. Structurally distinct PrP^Sc conformers can give rise to multiple prion strains. Constrained interactions between PrP^C and different PrP^Sc strains can in turn lead to certain PrP^Sc (sub)populations being selected for cross-species transmission, or even produce mutation-like events. By contrast, prion strains are generally conserved when transmitted within the same species, or to transgenic mice expressing homologous PrP^C. Here, we compare the strain properties of a representative sheep scrapie isolate transmitted to a panel of transgenic mouse lines expressing varying levels of homologous PrP^C. While breeding true in mice expressing PrP^C at near physiological levels, scrapie prions evolve consistently towards different strain components in mice beyond a certain threshold of PrP^C overexpression. Our results support the view that PrP^C gene dosage can influence prion evolution on homotypic transmission.